Research Report 2010 - MDC

Scientific-Technical StaffAnja Fritzsche*Ronny Kalis*Sandra NeuendorfStephanie PlaßmannKirstin RauAnke ThiemeFranziska Schiele*Martina ZenknerTechnical AssistantsNouhad Benlasfer*Anna Happe-Kramer*Daniela KleckersSusanne Köppen*Susanne RautenbergAlexandra RedelDana Rotte*Kati Scharf*Nancy SchugardtJan TimmCarsta Werner*Projekt Management(NGFN2 SMP Protein)Dr. Patrick Umbach*Project Management(NGFN-Plus/NeuroNet)Dr. Paul Schultze-Motel*aggregation intermediates into large amyloid structuresmight be a powerful therapeutic approach totreat protein misfolding diseases.In order to investigate whether the small moleculesthat modulate amyloid formation pathways in vitro andin vivo are useful for therapy development, a drug discoveryprogram for AD and HD was started in 2007 inthe framework of the GO-Bio initiative of the GermanFederal Ministry for Education and Research. The aim ofthis program is to promote the establishment of innovativestart-up companies out of the academic sector. Inthe first funding phase of the Go-Bio project, we havediscovered a number of novel drug candidates for bothAD and HD and developed them up to in vivo proof ofconcept in transgenic mouse models of the two diseases.At the moment, derivatisation and further in vivotesting are in progress in the framework of lead optimisation.Identification of proteins that modulate polyQmediatedhuntingtin aggregationHD is an inherited neurodegenerative disorder that iscaused by an expansion of a polyQ tract in the proteinhuntingtin, which leads to a characteristic accumulationof insoluble Htt aggregates in affected neuronsand eventually to cellular dysfunction and toxicity.However, the molecular pathways underlying brainspecific,polyQ-induced neurodegeneration in HD arestill unknown. Recently, a large number of interactionpartners were identified that associate with the N-terminaldomain of huntingtin, which harbours the aggregation-pronepolyQ tract. We hypothesized that perturbationof functional huntingtin protein complexes inneurons induces protein misfolding and neurotoxicity.To identify tissue-specific, dysregulated huntingtin proteininteractions, a bioinformatic approach was developed.By filtering publically available protein-proteininteraction (PPI) data with information from geneexpression studies of brain and non-brain tissues aswell as clinical case-control studies, a brain-specifichuntingtin PPI network was created, linking 14 potentiallydysregulated proteins directly or indirectly to thedisease protein. Analysis of published data confirmedthe predictive value of this network modelling strategy.Moreover, systematic investigations with in vitro andDrosophila model systems of HD demonstrated thatthe potentially dysregulated huntingtin interactionpartners influence polyQ-mediated protein misfoldingand neurodegeneration. The neuron-specific proteinCRMP1 e.g. is recruited to inclusion bodies with aggregatedhuntingtin protein in brains of HD transgenicmice and efficiently inhibits polyQ-mediated huntingtinexon 1 aggregation in cell free assays. Our resultsoffer a new strategy for identifying perturbed, tissuespecifichuman PPIs and modulators of protein misfoldingand aggregation (Bounab et al., 2009, submitted).Development of interactome databases andnovel quality standards for systematic proteininteraction studiesHuman protein interaction maps have become importanttools of biomedical research for the elucidation ofmolecular mechanisms and the identification of newmodulators of disease processes. We developed a comprehensiveinteractome database termed UnifiedHuman Interactome (UniHI). It provides researcherswith a comprehensive integrated platform to query andaccess human PPI data. Since its first release, UniHI hasconsiderably increased in size. The latest update ofUniHI includes over 250,000 interactions between~23,000 unique proteins collected from 14 majorsources. However, this wealth of data also poses newchallenges for researchers due to the size and complexityof interaction networks retrieved from the database.We therefore developed several new tools to query, analyzeand visualize human PPI networks. Most importantly,UniHI now allows the construction of tissue-specificinteraction networks and focused searches ofcanonical pathways. This will enable researchers to targettheir analysis and to prioritize candidate proteinsfor follow-up studies. UniHI 4 can be accessed athttp://www.mdc-berlin.de/unihi (Chaurasisa et al.,2008).184 Function and Dysfunction of the Nervous System